Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection

详细信息    查看全文

• 作者：Katja Giersch ; Martina Helbig ; Tassilo Volz ; Lena Allweiss ; Lida V. Mancke ; Ansgar W. Lohse ; Susanne Polywka ; J枚rg M. Pollok ; J枚rg Petersen ; John Taylor ; Maura D ; ri ; Marc L眉tgehetmann
• 关键词：HDV ; hepatitis delta virus ; HBV ; hepatitis B virus ; cccDNA ; covalently closed circular DNA ; HBsAg ; HBV surface antigen ; HBcAg ; HBV core antigen ; HDAg ; hepatitis delta antigen ; USB ; uPA/SCID beige mice
• 刊名：Journal of Hepatology
• 出版年：March, 2014
• 年：2014
• 卷：60
• 期：3
• 页码：538-544
• 全文大小：1609 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferencesml version="1.0" encoding="UTF-8"?>

Background & Aims

Clinical studies have shown that hepatitis delta virus (HDV) infection can persist for years and intrahepatic latency of the large delta antigen (HDAg) has been detected following liver transplantation. However, large HDAg arising via RNA-editing is associated with increasing amounts of non-infectious HDV quasi-species. This study investigated whether HDV could persist intrahepatically in the absence of HBV m>in vivom> and whether infectious HDV could subsequently be released following HBV super-infection.

Methods

Humanized mice were infected with HDV particles lacking HBV. To test for rescue of latent HDV infection 3 and 6 weeks HDV mono-infected mice were super-infected with HBV. Viral loads and cell toxicity were determined by qRT-PCR and immunohistochemistry.

Results

The presence of HDAg-positive human hepatocytes determined after 2, 3, and 6 weeks of HDV inoculation demonstrated establishment and maintenance of intrahepatic HDV mono-infection. Although intrahepatic amounts of large HDAg and edited HDV RNA forms increased over time in HDV mono-infected livers, HBV super-infection led to prompt viremia development (up to 10⁸ HDV RNA and 10⁷ HBV-DNA copies/ml) even after 6 weeks of latent mono-infection. Concurrently, the number of HDAg-positive human hepatocytes increased, demonstrating intrahepatic HDV spreading. The infectivity of the rescued HDV virions was verified by serial passage in naive chimeric mice.

Conclusions

HDV mono-infection can persist intrahepatically for at least 6 weeks before being rescued by HBV. Conversion of a latent HDV infection to a productive HBV/HDV co-infection may contribute to HDV persistence even in patients with low HBV replication and in the setting of liver transplantation.